The hippocampal formation is a prominent region of the medial temporal lobe that has been implicated in the encoding of long term memory. In the course of this research program, we have conducted neuroanatomical studies of the intrinsic and extrinsic connections, and chemical neuroanatomy, of the rat and monkey hippocampal formation. These led to comprehensive neuroanatomical studies of the perirhinal, parahippocampal and retrosplenial cortices which are the main interfaces of the hippocampal formation with the neocortex. With this application, we enter a new phase of these studies. Emphasis will be placed on qualitative and quantitative comparisons between the rat and monkey, and the monkey and human hippocampal formation. We examine the hypothesis that there are fundamental cellular and network differences between the rodent and primate hippocampal formation. We will also begin a detailed analysis of the human hippocampal formation. Where feasible, comparisons will be made between monkey and human histology that is processed in exactly the same way. We propose to use an in vitro slice laboratory recently established at the California Regional Primate Research Center to conduct a unique series of electrophysiological and neuroanatomical studies of the neurons of the monkey hippocampal formation. In particular, we propose to determine the cellular morphology and biophysical properties of neurons in layers II and V of the entorhinal cortex; these data will be compared with recently completed studies of the same layers in the rat. We will also carry out quantitative analyses of granule and pyramidal cells in the monkey hippocampal formation for comparison with data previously acquired in the rat. We will evaluate the hypothesis that neuronal types and their connections are more heterogeneous in the primate hippocampal formation than in the rodent. The detailed organization of intrinsic hippocampal connections will also be studied by using the tracer Phaseolus vulgaris leucoagglutinin; we will focus on the connections from the dentate gyrus to the hippocampus, from the CA3 field to the CA1 field, and from the CA1 field to the subiculum. Results of these studies will also be compared with those from earlier rat studies. Finally, we will carry out detailed cytoarchitectonic analyses of the human hippocampal formation using standard staining methods as well as immunohistochemical and in situ hybridization techniques for the demonstration of GABA. These data will provide essential information on the functional organization of the primate hippocampal formation with implications for studies of normal memory and human disorders such as epilepsy and autism.